CLL Support Association
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Ibrutinib as frontline??

Hello everyone!

Does anyone know why Ibrutinib is only available to CLL patients whose previous treatments have been unsuccessful?

It was first made routinely available to leukaemia patients through the NHS in 2016, apparently after years of campaigning by Bloodwise, the cancer research charity.

I've read posts on here which seem to claim that the new immunotherapies such as Ibrutinib have a better outcome when used as a first treatment, instead of FCR.

Also that the residual toxiticies of FCR, negatively affect ibrutinib.

I believe it's a particularly expensive drug, so maybe it's the NHS trying to save money?

Bendintheroad1

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From the NICE website, July 5, 2017

'NICE is unable to make a recommendation about the use in the NHS of ibrutinib for untreated chronic lymphocytic leukaemia without a 17p deletion or TP53 mutation because no evidence submission was received from Janssen–Cilag. We will review this decision if the company decides to make a submission.'

nice.org.uk/guidance/ta452

From this Janssen hasn't submitted... 🙁

There is no evidence that ibrutinib is better than FCR, in firstline use. Better how? Less toxic, longer remissions? We do know that MRD negativity is harder to achieve on ibrutinib than on FCR ... does it matter? Don't know.

Its very early days for Imbruvica (ibrutinib) firstline use... in the U.S.

~chris

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Actually there's good evidence that ibutrinib is more effective than FCR as a first line agent, both for 17p deletion, and for unmutated patients. If FCR is used with unmutated patients, the relapse rate is high, and the ibrutinib is less effective because of clonal evolution.

Ileana

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And this is where Ibrutinib is (sometimes) getting approval over FCR use when Janssen submits requests. Don't forget that FCR is over and done with in 6 months - a fixed cost, whereas Ibrutinib is still needed for an indeterminate time, plus we have around 3 times the length of data for FCR - 15 years compared to 5 and we know about 15% of patients on Ibrutinib develop atrial fibrillation - that's about 1 in 6 patients needing further medical intervention...

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Yes! May I ask you where I can read about this evidence that Ibrutinib is more effective than FCR as a first line agent?

Particularly interested in suitability for unmutated patients. Also, wonder why NICE says on website that they have no such evidence from Janssen-Cileg, the producers.

Thank you.

Bendintheroad1

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Thanks for this Chris! Well better I guess because it's not a chemotherapy and the new immunotherapies of which I believe Ibrutinib is one, seem to be hailed as the way ahead with fewer side effects and directly targeted at B cells meaning not so much collateral damage. Expensive though, so understandable that NICE might be prudent and not pushing the drug company to see if they can provide evidence of effectivity with untreated CLL.

Best to you

Trevor

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Give some thought that insurance companies also have a say in the progression of drug therapies. i went through two drugs before Ibrutnib was prescribed. Now Ibrutnib is done because I developed afib and atrial fluttering. Next I will be taking Zeliug, another Janssen drug that does not have a heart side effect.

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I went on Imbruvica (ibrutinib), briefly, then switched to Zydelig (idelalisib) and rituxan..and it has been fine.. very minor side effects. That was a year ago and my counts were all in range...

However you need to be monitored closely and take the necessay prophylactic medicines, required for patients in idealisib.

~chris

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Chris -

I cannot believe I may have reached an actual person with some experience that I need to know about. I had excellent results for remission on Ibruvica but then it turned nasty and I developed afib and atrial flutters so I had to stop Ibrutnib. ......................

Now I am to start Zydelig - the doctor has told me nothing about prophylactic medicines for use with Zydelig. She did talk about frequent blood tests but without further explanation. Are frequent blood tests an ongoing thing? Can you tell me more about what you have had to do on Zydelig?

Since now I am on a blood thinner because of the afib I am concerned about the bleeding aspect of Zydelig on top of the Xarelto. What do you think? Jeanie in Pa.

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Ok... I will try... I was on Imbruvica (ibrutinib) for a short time and it cause bad bleeds and cranked up my prexisting A.fib

I was on the combination of Xarelto and Imbruvica (ibrutinib) ...

I quit Imbruvica (ibrutinib) to deal with colon cancer and floated about 15 months with no CLL treatment.. them my Hgb tanked... then the next week Zydelig (idelalisib) was funded where I reside. 😁

So I started Rituxan infusions every two weeks for 8 rounds...then Zydelig (idelalisib) was added in round two.

The drug label is very specific about prophelactics, your doctor needs to read it.

I was monitored monthly by my CLL specialist, with blood draws. They also did draws at each infusion.

The concerns seen in clinical trials were CMV, reactivation and fungal pneumonia called PCP or PJP, hepatotoxicity, rashes.

So the CMV is a special blood test part of monitoring. Septra or Bactrim antibiotics are used to prevent PJP.. yes an antibiotic prevents a fungal infection.. go figure...

Again liver needs close monitoring... through blood.

My absolute lymphocyte count [ALC] was over 400K so I was on allopurinol to prevent tumor lysis.

Side effects... for me a week or 2 of diarrhea and after a year a few of my fingernails have gotten very thick, but not splitting.

The treatment had no impact on my heart and I'm still on Xarelto. Bleeding was not an issue.

I'm including a link to the drug label, but please do not read it unless you understand that some of the adverse events are quite rare.

Like Imbruvica (ibrutinib) no grapefruit or St. John's Wort etc, and EVERY supplement or drugs prescribed by other doctors, needs to be vetted by your CLL doctor...

dailymed.nlm.nih.gov/dailym...

Final thought.. I was on the Furman/Sharman protocol, there may be others...

Here are the trial data

nejm.org/doi/pdf/10.1056/NE...

~chris

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Thank you. I was on Imbrutnib for five month with great results but then it went into afib and I had to stop. Now the drug of choice is going to be Zydelig. I also had terrible mental confusion on Imbrutnib. I am concerned that the Xarelto and the Zydelig both cause bleeding and fatigue. I have come to believe that most of my tiredness is now caused by the medications rather than the NHLymphoma. Thank you for sharing your experience with me.

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Ibrutinib was approved by Nice for second line treatment in GB for CLL in January/February 2017.

Not only does Bloodwise do a good job of campaigning

On our behalf so does the CLLSA. Ijust thought I would like to mention this fact. A lot of time and effort is put in that maybe we are not fully aware of.

Best wishes.

Sue

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Here here! Personally I'm very grateful and more secure in the knowledge that these good people make so many breakthroughs!

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Thank you for that wroxham-gb. Some of us spent a lot of time writing and making the necessary submissions to help to get the right result.

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The UK FLAIR study is trying to address the issue of evidence around FCR v IR in first line treatment for non 17p deleted or TP53 patients (they are excluded). Patients were randomised initially on a 1:1 basis but the trial has been extended recently to include 2 new arms.

Recruitment started August 2014 so early results should be coming in the next few years. Janssen has paid for the Ibrutinib for that arm of the study for 6 years, many millions of pounds.

Clinical trials can take many years to produce the evidence to change practice, particularly when the differences only become apparent over years and with large numbers of patients. In that time the question they are trying to answer is in danger of being made irrelevant or overtaken by new technology/drugs as things are moving so quickly these days.

Ibrutinib for all new patients could put a big hole in NHS budgets whereas FCR is cheap and over in 6 months with no ongoing costs. This is where the health economists have to balance the needs and well being of all patients in the NHS, it's a tough one.

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Ibrutinib is first line treatment here in US. Cost is picked up by a foundation & Leukemia & Lymphonia Association.

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Is the cost pick up for all patients even front line? I'm still on WW but likely to be treated in a couple of years. Have SLL with some migration into the blood. Deleted 13q. Given other issues I'm likely a candidate for ibutrinib or something else along those lines.

Hope everyone has a good day, however defined, today!,

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Sorry i did not finish my reply. Ibrutinib given to me as 1st line (treatment naive). Don't be in a rush to start med.

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The expense of Imbruvica (ibrutinib) treatment in the U.S. is picked up by either private insurance or government plans like Medicare, Medicaid.

The out of pocket expense portion called copay may be paid by others including the drug company in some cases, the Leukemia & Lymphoma Society and other groups like PAN, but its a tiny portion compared to the $105,000 annual cost of the drug.

PAN

panfoundation.org/index.php...

~chris

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Medicare in the US does not pick up the cost of ibtrunib because it is administered as an injection or infusion in a clinic, docs office etc. They don't pay for pills unless they were originally infused etc. Go figure🤑

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Meant to say NOT administered in clinic etc

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Imbruvica (ibrutinib) is covered first and second line in the U.S. for patients on Medicare with supplementary coverage. [Part D].. Copay assistance availability is based on income...

This website may be of value to you

medicare.gov

~chris

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Thanks . Agree that your part d or other source like an association can certainly help defray the $140,000 est annual cost. On part D you have to make sure the insurance company has it approved as part of its formulary but it will still cost you re part B , part D the "gap"and any deductibles prior to reaching the defined catastrophic levels.

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Its $105,000 ..it just went up last fall...

If you have private insurance , not Medicare, then you may get relief from the You & I program. I was on this briefly in Canada... lots of hoops you need to jump through, but it worked our fine...

imbruvica.com/you-i-support

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Thanks. The hoops are worth it, literally.

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On the US it is frontline.

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11q del and unmutated was not a negative factor with Ibrutinib as it is with FCR. Thus for that population and 17del Ibritinib seems to be superior. At least thats what I glean from my readings of top doc opinions.

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RESONATE : second line data ( in older pts 40% of patients >70 yo)

A follow-up study of the RESONATE phase III trial provides further support that ibrutinib, an inhibitor of Bruton tyrosine kinase, achieves greater progression-free survival (PFS) than ofatumumab, a high overall survival (OS) rate, and high tolerability among patients with chronic lymphoid leukemia (CLL) who have had at least one prior treatment. The most recent results of the RESONATE (PCYC-1112) trial, which were based on a median follow-up time of 44 months, were presented in a Poster Session (Abstract 7510) on June 5.

In the RESONATE trial, 391 patients with relapsed/refractory CLL were randomly assigned to receive 420 mg of oral ibrutinib once a day until disease progression or unacceptable toxicity occurred or intravenous ofatumumab for up to 24 weeks.1 At the interim analysis with a median follow-up time of 9 months, the disease had progressed in all but one of the patients taking ofatumumab, and those patients crossed over to the ibrutinib group.

At 3 years, when nearly all of the participants were receiving ibrutinib, the OS for the drug was 74%, and the PFS after a median of 44 months was 59%. The overall response rate was 91%; the rate of complete response or complete response with incomplete hematologic recovery was 9% and increased with time.

“These data definitively demonstrate that ibrutinib is a better therapy [than ofatumumab] for relapsed and refractory CLL,” presenter John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, said.

The data also confirm that the response to ibrutinib improves over time, and its performance in the phase III trial confirmed the results of the phase II PCYC-1102-CA trial that led to the accelerated approval of the drug for relapsed/refractory CLL by the U.S. Food and Drug Administration in 2014, Dr. Byrd said. The results of another phase III trial, RESONATE-2 (PCYC-1115-CA),1 led to the approval of ibrutinib in 2016 for patients with CLL who had no prior treatment.

“With extended follow-up, we see that patients receiving ibrutinib have for virtually every side effect diminishing occurrence, including infections. That speaks to the drug improving the immune system of patients over time,” Dr. Byrd said. For example, skin rash and loose stool, which are often seen early in treatment, decreased in frequency after patients were on ibrutinib for several years, he said.

After 44 months of follow-up, 46% of patients in the trial remained on ibrutinib, 27% of them discontinued treatment because of disease progression, and 12% discontinued because of adverse events. The incidences of major hemorrhage and grade 3 or greater atrial fibrillation were each 6%.

Although the incidence of most grade 3 or greater adverse events decreased over time, the incidence of hypertension increased from 8% among patients the first year on ibrutinib to 23% after more than 2 years. “This is clearly an emerging toxicity over time to be aware of when you use ibrutinib,” Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute, said during the Poster Discussion Session.

Dr. Brown noted that discontinuation rates for ibrutinib may increase with age and pointed to a retrospective analysis that suggested that discontinuation rates in clinical practice may be as high as 42% after a median of 7 months on the drug. She said that the higher rate could be related to differences between patients in clinical practice and in trials.

Among the unmet needs of ibrutinib were subgroups of patients with CLL who have mutations that are associated with early relapse, such as those with deletions in the 17p chromosomal arm, Dr. Brown said. The RESONATE trial follow-up found that patients who have deletions in the 11q chromosomal arm trended toward better PFS than those with deletions in 17p, but the difference was not statistically significant.

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“With extended follow-up, we see that patients receiving ibrutinib have for virtually every side effect diminishing occurrence, including infections. That speaks to the drug improving the immune system of patients over time,” Dr. Byrd said.

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Yep. Have seen these things, but Ibrutinib is not available in U.K. for untreated CLL.

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Hopefully it is approved for Frontline soon. Provided one does not have bad side effects it is much more gentle on the body for the long term in my opinion.

I think this graph says a lot:

Unfortunatley they took down the video from Ohio state.

healthunlocked.com/cllsuppo...

.

Hoffy

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